Aerobic Interval Training and Continuous Training equally improve aerobic exercise
capacity in patients with Coronary Artery Disease: The SAINTEX-CAD study
Running title: Interval versus continuous training in CAD patients
Viviane M. Conraads 1,2 †
Nele Pattyn 3*
Catherine De Maeyer 1,2*
Paul J. Beckers 1,2
Ellen Coeckelberghs 3
Véronique A. Cornelissen 3
Johan Denollet 1,4
Geert Frederix 1,5
Kaatje Goetschalckx 3,6
Vicky Y. Hoymans 1,2,5
Nadine Possemiers 1
Dirk Schepers 3
Bharati Shivalkar 1,2
Jens-Uwe Voigt 6
Emeline M. Van Craenenbroeck 1,2,5
Luc Vanhees 3,6,
† Prof. V. Conraads passed away on 12/12/2013
1 Department of Cardiology, Antwerp University Hospital, Edegem, Belgium
2 University of Antwerp, Antwerp, Belgium
1
3 Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium
4 CoRPS-Centre of Research on Psychology in Somatic diseases, Tilburg University,
Tilburg, The Netherlands
5 Laboratory of Cellular and Molecular Cardiology, Antwerp University Hospital,
Edegem, Belgium
6 Department of Cardiovascular Diseases, University Hospitals of Leuven, Leuven,
Belgium
[email protected]; [email protected]; [email protected];
[email protected]; [email protected];
[email protected]; [email protected]; [email protected];
[email protected]; [email protected]; [email protected];
[email protected]; [email protected];
[email protected]; [email protected]
All authors take responsibility for all aspects of the reliability and freedom from bias of the
data presented and their discussed interpretation.
* Authors contributed equally
Name and address for correspondence
Luc Vanhees
Department of Rehabilitation Sciences
Tervuursevest 101, B 1501
B 3001 Heverlee
2
Belgium
Tel: +32-16-329158
Fax: +32-16-329179
E-mail address: [email protected]
Acknowledgement of grant support: This work was funded by the Agency of Innovation by
Science and Technology (IWT-project number 090870).
Conflicts of interest to declare: none
Keywords: exercise intensity, training modality, coronary artery disease, secondary
prevention, cardiac rehabilitation, endothelial function
Word count: 5948 (including abstract, introduction, methods, results, discussion, references)
Number of tables and figures: 4 tables and 3 figures, 2 supplemental tables
3
Abstract
BACKGROUND Exercise-based cardiac rehabilitation increases peak oxygen uptake (peak
VO2), which is an important predictor of mortality in cardiac patients. However, it remains
unclear which exercise characteristics are most effective for improving peak VO2 in coronary
artery disease (CAD) patients. Proof of concept papers comparing Aerobic Interval Training
(AIT) and Moderate Continuous Training (MCT) were conducted in small sample sizes and
findings were inconsistent and heterogeneous. Therefore, we aimed to compare the effects
of AIT and Aerobic Continuous Training (ACT) on peak VO2, peripheral endothelial function,
cardiovascular risk factors, quality of life and safety, in a large multicentre study.
METHODS Two-hundred CAD patients (LVEF >40%, 90% men, mean age 58.4 ± 9.1 years)
were randomized to a supervised 12-week cardiac rehabilitation program of three weekly
sessions of either AIT (90-95% of peak heart rate (HR)) or ACT (70-75% of peak HR) on a
bicycle. Primary outcome was peak VO2; secondary outcomes were peripheral endothelial
function, cardiovascular risk factors, quality of life and safety.
RESULTS Peak VO2 (ml/kg/min) increased significantly in both groups (AIT 22.7 ± 17.6%
versus ACT 20.3 ± 15.3%; p-time<0.001). In addition, flow-mediated dilation (AIT +34.1%
(range -69.8 to 646%) versus ACT +7.14% (range -66.7 to 503%); p-time<0.001), quality of life
and some other cardiovascular risk factors including resting diastolic blood pressure and
HDL-C improved significantly after training. Improvements were equal for both training
interventions.
CONCLUSIONS Contrary to earlier smaller trials, we observed similar improvements in
exercise capacity and peripheral endothelial function following AIT and ACT in a large
population of CAD patients.
4
5
Introduction
Coronary artery disease (CAD) is the main cause of death worldwide1 and in Europe.2 The
benefits of exercise-based cardiac rehabilitation on cardiovascular risk factors,3,4 on quality
of life (QoL),5 on exercise tolerance (peak VO2),6-9 and on cardiac morbidity and mortality3,4
have been widely established in CAD patients. However, there is still controversy regarding
the optimal exercise characteristics that yield the most beneficial effects in patients with
CAD.10,11 The “traditional” approach is to prescribe training at an intensity of 60 to 80% of
peak VO2, which results in an average increase of 20% for peak VO2.12 Intensity seems to be
an important predictor of the effectiveness of cardiac rehabilitation programs since a higher
intensity leads to larger improvements in peak VO2, even after adjustment for other training-
related variables.12,13 However, a higher intensity is difficult to maintain for a longer period;
therefore an interval structure is suggested by Mezzani et al.11 Interval training consists of
periods of high-intensity exercise alternated by periods of relative rest that make it possible
for patients to complete short work periods at higher intensities. From a physiological point
of view, high intensity interval training stimulates cardiac contractility and poses a larger
impact on the endothelium and skeletal muscle mitochondrial function compared to
continuous training at moderate intensity (MCT), which could add to a more favourable
effect on peak VO2.14 Whereas the implementation of high intensity aerobic interval training
(AIT) is common practice in sports medicine, only relatively small, single centre trials have
tested this approach in CAD patients.15,16 A recent meta-analysis, comprising 9 studies and
206 patients, concluded that AIT results in a 1.60 ml/kg/min larger benefit in peak VO 2
compared to MCT in patients with CAD.16 The AIT group showed an improvement of 20.5% in
peak VO2 compared to only 12.8% in the MCT group, the latter being low compared to the
average increases after three months of “traditional” cardiac rehabilitation.12 Given the small
6
sample sizes and the large inconsistency and heterogeneity between the study results, this
meta-analysis highly recommended that a sufficiently powered randomized multicentre
study is warranted to 1) assess efficacy and safety of AIT,16 and to 2) investigate if the aerobic
continuous training (ACT) can be performed at intensities higher than 70-75% of peak heart
rate (HR) resulting in better improvements.
Therefore, the aim of the present study17 was to assess whether a 12-week program of three
weekly, supervised sessions of AIT is superior to aerobic continuous training (ACT) in terms
of 1) peak VO2, 2) peripheral endothelial function, 3) cardiovascular risk factors, 4) QoL and
5) safety.
Methods
A detailed description of study design, eligibility and participants of the Study on Aerobic
INTerval EXercise training in CAD patients (SAINTEX-CAD) has been published previously.17
Participants
Two hundred CAD patients (aged between 40 – 75 years) referred for cardiac rehabilitation
were enrolled in a longitudinal, randomized prospective clinical study at the University
Hospital of Antwerp (Centre 1) and the University Hospital of Leuven (Centre 2), 100 patients
at each site. Inclusion criteria were:17 1) angiographically documented CAD or previous acute
myocardial infarction (AMI), 2) left ventricular ejection fraction (LVEF) > 40%, 3) on optimal
medical treatment, 4) stable with regard to symptoms and medication for at least 4 weeks
and 5) included between 4 and 12 weeks following AMI, Percutaneous Coronary
Intervention (PCI) or Coronary Artery Bypass Grafting (CABG). After obtaining written
informed consent, patients were randomized to AIT or ACT on a 1:1 base. The study
7
complied with the World Medical Association Declaration of Helsinki on ethics in medical
research18 and was approved by the local medical ethics committees.
Measurements
Anthropometric measurements, echocardiography and blood analyses were performed at
baseline and after 12 weeks. The cardiopulmonary exercise test (CPET), flow-mediated
dilation (FMD) and QoL were assessed at baseline, 6 weeks and 12 weeks. The CPET at 6
weeks was performed to adjust the training intensity according to the achieved peak HR.
Anthropometric measurements
Height (cm) and weight (kg) were measured before the CPET using a stadiometer (Seca
model) and a scale (Centre 1, ADE; Centre 2, Tefal, Sensitive Computer). Body mass index
(BMI) was calculated as the weight (kg) over the height squared (m²). Waist circumference
(cm) was measured end-expiratory at a level midway between the lowest rib and the iliac
crest.
Cardiopulmonary exercise test
As described previously,17 a maximal graded exercise test (20 Watt + 20 Watt/min or 10 Watt
+ 10 Watt/min) on a bicycle ergometer was performed. Twelve-lead ECG and gas exchange
measurements were recorded continuously, and blood pressure was measured every two
minutes. Peak VO2 was determined as the mean value of VO2 during the final 30 seconds of
exercise.
Flow-mediated dilation by brachial artery ultrasound scanning
8
Endothelium-dependent and -independent vasodilation of the right brachial artery were
measured by ultrasound scanning, (Centre 1, AU5 Ultrasound System, Esaote; Centre 2, GE
Healthcare, Vivid 7), in standardized conditions as described in the guidelines.19 A high
resolution linear-array vascular probe was used (Centre 1, 10 MHz; Centre 2, 5-13 MHz).
Patients were positioned supine with the right arm resting on an arm support; the brachial
artery was imaged above the antecubital fossa in the longitudinal plane. Blood pressure was
obtained after 10 minutes of rest with an automated blood pressure monitor (Omron M6).
To determine the endothelium-dependent vasodilation, the forearm was occluded for 5
minutes at a cuff pressure of at least 200 mmHg or 60 mmHg higher than the resting systolic
blood pressure. Images were continuously recorded before cuff inflation for 1 minute, and
after cuff deflation for 3 minutes. Endothelium-independent vasodilation was measured
after administering 1 dose (0.4mg) of nitroglycerine (Nitrolingual® Pumpspray) sublingually.
Images were continuously recorded from the 3rd until the 9th minute after administering
nitroglycerine. Images were analysed using edge-detection software FMD-i by Flomedi
(Flomedi, Brussels, Belgium). FMD and Nitroglycerine-mediated dilation (NMD) were
expressed as the change in post-stimulus diameter as a percentage of the baseline diameter.
Analyses were blinded in both study centres.
Echocardiography
Patients were examined by experienced cardiologists, at rest in the left lateral supine
position using an ultrasound machine (Centre 1, GE Healthcare, Vivid 7; Centre 2, GE
Healthcare, Vivid E9) and a 1.5-4.5 MHz probe. Left ventricular ejection fraction (LVEF) was
calculated using the biplane Simpson’s method on the 4- and 2-chamber views of the left
9
ventricle. The average of these two measurements was used in the statistical analysis.
Analyses were blinded and were performed by one cardiologist (CDM).
Blood analyses
Venous blood samples were drawn after an overnight fast. Total cholesterol, serum
triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein
cholesterol (LDL-C), and glucose were analysed by the biochemical laboratories using
standard procedures at both University Hospitals. High sensitivity C-Reactive Protein (hs-
CRP) was analysed using standard procedures in Centre 1 on all blood samples. Laboratory
personnel were blinded to treatment allocation.
Quality of Life
The Short Form-12 (SF-12) was used as a generic health status measure20 and comprises a
physical component summary (PCS) and a mental component summary (MCS) that refer to
self-reported physical and mental health status, respectively.21
Safety
All adverse events were reported immediately to the project coordinating committees
(Safety Committee and Adverse Event Committee) composed of two independent
researchers for each committee. Adverse events were defined as all-cause mortality,
hospitalization for cardiovascular disease, atrial tachycardia, atrial fibrillation or frequent
ventricular arrhythmias.
Exercise training
10
The training intervention (Figure 1) was previously described by Conraads et al.17 In short,
patients followed a supervised training program for 3 times a week during 12 weeks of either
AIT (90-95% of peak HR) or ACT (at least 70-75% of peak HR) on a bicycle (Centre 1,
Technogym XT; Centre 2, Ergo-fit, Gymna). Besides 36 exercise sessions, 6 additional multi-
disciplinary education sessions were organized.
Patients in Centre 1 exercised using a key, in which their target HR zones were programmed.
The key was connected to the bicycle, and workload was adapted continuously according to
the actual training HR. In Centre 2, a workload-based approach was used, where workloads
were determined for each training session, and HR was measured 4 times during each
session. If the HR was no longer close to the upper border of the target HR zone, the
workload for the next session was adapted. The Borg 6–20 scale and blood pressure were
measured after each training session.
Statistical analyses
Data are presented as mean ± standard deviation (SD) or as number; in the figure mean ±
standard error of measurement (SEM) was used. All statistical analyses were performed
using SAS (SAS® 9.3, Sas Institute, Inc., Cary, NC, USA). Based on an effect size of 0.5
(increase in peak VO2 of 3.5 ml/kg/min, SD 7 ml/kg/min), we calculated that a total number
of 172 patients would be needed to detect a larger benefit with AIT, with a significance level
of 0.05 and a statistical power of 0.90.17 To anticipate for potential drop-outs, 100 patients
were enrolled in each treatment arm.
Baseline characteristics were calculated for the total group and the AIT and ACT group
separately. Group differences and differences between inclusions and non-inclusions were
tested by ANOVA for continuous variables and by chi- square test for dichotomous variables.
11
As there were group differences for age and pathology (Acute Myocardial Infarction (AMI),
Coronary Artery Bypass Surgery (CABG) and Percutaneous Coronary Intervention (PCI)) at
baseline, an ANCOVA was performed to test the effects after 6 and 12 weeks of training with
age and pathology as covariates. Patients who had only AMI or AMI+PCI, were categorized in
the AMI group. The CABG group comprised all patients who had CABG, AMI+CABG, or the
combination of AMI+PCI+CABG. The PCI group consisted of patients that only had PCI. The
Scheffé test for multiple comparisons was used as post hoc test. Pearson correlation
coefficients were calculated between baseline values and changes of the primary outcome
peak VO2 (ml/kg/min) and secondary outcome FMD (%).
For the primary and secondary outcome (peak VO2 in ml/kg/min and FMD in %), the effect of
the centre of enrolment was calculated using an ANCOVA with centre as covariate, in
addition to age and pathology. No centre-effect was found for peak VO2 (p=0.81) but FMD
resulted in a significantly higher mean value in Centre 2 (p<0.001). Therefore, ANCOVA for
FMD included age, pathology and centre as covariates. Percentual changes of FMD were
skewed and therefore expressed as median and range.
Intention-to-treat analysis,22 in which the results from all patients assigned to AIT or ACT
were taken into account, including drop-outs, was done for the primary outcome (peak VO2
in ml/kg/min). The baseline data of the drop-outs were used as the missing data at 6 and/or
12 weeks of the intervention. This intention-to-treat analysis usually reflects the effects of
treatment in everyday practice. As we aimed to investigate the results of the treatment, we
performed a per protocol analysis for the training effects.
All statistical tests were 2-sided at a significance level of ≤0.05.
Mean training HR and workloads for session 1 to 18 and 19 to 36 were calculated by
averaging the four HRs/workloads of each training session (AIT: HR/workload measured at
12
the end of each 4-minute interval; ACT: HR/workload measured at 10’, 20’, 30’ and 37’ of the
moderate intensity bout) and dividing it by the number of training sessions (= 18). These
mean HRs/workloads were expressed as % of the peak HR/workload of the first exercise test
(peak HR 1 / workload 1) for session 1-18 and of the second exercise test (peak HR 2 /
workload 2) for session 19-36.
Hs-CRP values were not detectable if <0.160 mg/l and these values were thus replaced by
0.160 mg/l. In addition, hs-CRP data were skewed and were therefore log transformed
before analyses.
13
Results
A flowchart of the trial is presented in Figure 2. One thousand thirty seven patients were
referred to cardiac rehabilitation between November 2010 and March 2013 (Centre 1, n =
392; Centre 2, n = 645). Four hundred seventy seven patients were eligible according to the
inclusion and exclusion criteria,17 of which 175 refused participation, 102 could not be
included for other reasons, and 200 were randomized to AIT or ACT. Age was not
significantly different (p=0.23) between the included patients (n = 200) and the eligible but
non-included patients (n = 277), respectively 58.4 ± 9.1 years versus 59.4 ± 8.9 years, but
significantly (p=0.0035) less females were included (included: 180 M and 20 F versus non-
included: 222 M and 55 F): 45% of all men compared to 27% of all women participated.
Baseline characteristics of the included patients are presented in Table 1. Age and pathology
differed significantly, with younger age, more post-AMI and less post-PCI patients in the AIT
group, while other baseline values were similar between AIT and ACT.
As shown in Figure 2, 26 patients dropped out (13%) during the 12 weeks of training, of
which 15 from the AIT group (6 in Centre 1; 9 in Centre 2; NS) and 11 from the ACT group (5
in Centre 1; 6 in Centre 2; NS). The drop-out rate in women (7 out of 20; 5 AIT and 2 ACT)
was higher than the drop-out rate in men (19 out of 180; 10 AIT and 9 ACT; p=0.002).
According to previous calculations,17 a number of 174 patients was still sufficient to detect
significant differences between AIT and ACT.
As shown in Table 2, peak VO2, peak workload, peak HR and O2pulse increased significantly
over time (p<0.001). Similar responses were found after AIT and ACT. Peak VO2 increased
with 14.5 ± 20.1% after 6 weeks and 22.7 ± 17.6% after 12 weeks of AIT; peak VO2 improved
with 13.1 ± 12.8% after 6 weeks and 20.3 ± 15.3% after 12 weeks of ACT (Figure 3). Results of
14
the intention-to-treat analysis for peak VO2 did not differ significantly from the per protocol
analysis.
We observed a significant increase in FMD following training with no difference between
both training groups (Table 3). Flow-mediated dilation increased with 12.3% (range -78.9 to
454%) after 6 weeks and 34.1% (range -69.8 to 646%) after 12 weeks of AIT; FMD increased
with 16.9% (range -80.8 to 503%) after 6 weeks and 7.14% (range -66.7 to 503%) after 12
weeks of ACT. Baseline FMD was inversely correlated with changes in FMD (r=-0.51;
p<0.001). Changes in peak VO2 (ml/kg/min) correlated significantly with changes in FMD
(r=0.17; p=0.035).
As shown in Table 4, HDL-C and total cholesterol increased significantly after the 12-week
intervention, with no difference between both training groups. Diastolic blood pressure and
hs-CRP decreased significantly over time, while systolic blood pressure tended to decrease.
Quality of life improved significantly on the physical and mental domain following AIT and
ACT, with no group differences (Table 4). Increases from baseline to 6 weeks were
significant, with no further significant improvements from 6 to 12 weeks (data at 6 weeks
not shown).
Beta-blocker dose was changed in 32 patients during the intervention period: the dose was
doubled in 17 (5 AIT, 12 ACT) and halved in 8 (5 AIT, 3 ACT), stopped in 3 (1 AIT, 2 ACT) and
started in 4 (2 AIT, 2 ACT) patients. When excluding these 32 patients, similar results were
found for all exercise- and endothelial-related variables, for cardiovascular risk factors and
QoL, except for resting diastolic blood pressure (p-time>0.05).
Overall compliance for the AIT group was 35.7 ± 1.1 training sessions and for the ACT group
35.6 ± 1.5 training sessions. The analyses of the training intensities were done for the total
15
group of patients (n = 172), as it did not differ from the analyses excluding patients changing
their beta-blocker dose. Mean training intensity for the AIT group was around 88% of peak
HR and for the ACT group around 80% of peak HR during the 12 week intervention
(Supplemental Table 5). Mean training workloads for the AIT group were 86% of peak
workload and for the ACT group 63% of peak workload. (Supplemental Table 6) There were
significant group differences between the training intensities (p-group<0.001), the training
workloads (p-group<0.001) and the Borg scores (p-group<0.001; AIT: 13.5 ± 1.6 vs ACT: 12.5
± 1.5), with higher values for the AIT group.
No adverse events were reported during the training sessions. One patient (ACT) had an
AMI, >24 hours after his last training session, after which PCI was performed. Two other
patients (both ACT) had significant ST-depression during the exercise test at 6 weeks and
underwent PCI.
16
Discussion
Exercise training is a cornerstone in cardiac rehabilitation; however, there is still controversy
regarding the exercise characteristics that are most effective for improving peak VO2 in CAD
patients.10 Proof of concept papers comparing AIT and MCT were conducted in small sample
sizes and findings were inconsistent and heterogeneous.16 The results of the present large
randomized multicentre study in CAD patients demonstrate that AIT and ACT are equal in
improving peak VO2, peripheral endothelial function, QoL, and some cardiovascular risk
factors. In addition, both programs seem to have beneficial effects within the first six weeks
of training and are safe in CAD patients.
Peak VO2 increased with 5.06 ± 4.06 ml/kg/min or 22.7 ± 17.6% after AIT and with 4.35 ±
3.21 ml/kg/min or 20.3 ± 15.3% after ACT. These increases are probably of clinical relevance,
as suggested by a large observational study, where each 3.5 ml/kg/min increment in peak
VO2 resulted in a 12% improvement in survival..7 This 22.7% increase in peak VO2 after AIT is
comparable to the increments reported in the meta-analysis of Pattyn et al.16 (20.5%) and to
other large intervention studies,12,23 while the 20.3% increase after ACT in our study is larger
than the 12.8% increase in peak VO2 described in the same meta-analysis.16 The difference
with earlier publications might be explained by the on average lower training intensity
observed in these ACT groups16 (range 70-75% of peak HR) resulting in relatively lower gains
in peak VO2. Analyses of the present study showed that our ACT group trained at average
intensities of 80% of peak HR. The fact that none of the patients had to terminate the
exercise prematurely suggests that they were still working aerobically. We can conclude for
ACT that if a higher intensity can be sustained, the workloads and HR zones need to be
adapted to achieve the best improvements possible.
17
In contrast, the average intensity of the AIT group was 88% of peak HR, which is lower than
the prescribed intensity. In practice, we had to decrease training intensity in several patients
in order to avoid extreme hyperventilation or discontinuation of pedalling. In accordance
with our results, Guiraud et al. demonstrated that a shorter high-intensity interval (15s) was
at least as efficient in the time spent at peak VO2 and much better tolerated than the longer
ones (60s) in CAD patients.24 However, our patients in the AIT group perceived shortness of
breath and scored significantly higher on the Borg scale than the ACT group. Though, we
think that the results of the Borg scale were not reliable and did not reflect real exercise
intensity. This is in agreement with a recently published paper,25 in which the authors
concluded that rating of perceived exertion results in an exercise intensity below target
(Borg score 17) during high-intensity interval training bouts, and that HR monitors should be
used for accurate intensity guidance. We can conclude that AIT training at 90-95% of peak
HR is hardly feasible in most of the CAD patients, at least not for the full four minutes.
Nevertheless, if we calculated the relative intensity of session 19-36 using peak HR1, patients
in the AIT group trained at >90% of peak HR1, as prescribed (Supplemental Table 5). Since
peak HR increased (Table 2) following training, target HR zones needed adaptation. The
relative intensity of session 19-36 was only 84% of peak HR3 (Supplemental Table 5), which
suggests that not changing the target HR zones result in low intensities of training and
probably smaller improvements after the intervention.
Following these results and observations we suggest that in clinical practice, it is necessary
to adjust the objectively defined target HR zones and workloads according to the patient’s
subjective feelings as11 1) ACT programs can be sustained at intensities higher than 70-75%
of peak HR, and 2) AIT programs with 4-minute intervals at 90-95% of peak HR are hardly
18
feasible for four minutes. Further we recommend an intermediate exercise test to adapt
target HR zones.
Endothelial dysfunction is an important early precursor of atherosclerosis and is an
independent predictor of cardiovascular events.26 Previous studies have shown that FMD
improves after exercise-based cardiac rehabilitation in CAD patients.27-29 In accordance to our
results, Currie et al.30 found similar improvements after AIT and MCT, while Wisloff et al.14
and Tjonna et al.31 found larger increases after AIT compared to MCT. At the moment, there
is no consensus for a clinical relevant cut off value for brachial artery FMD.32 However, it has
been shown that persistent impairment of FMD, defined as FMD <5.5%, is an independent
predictor of cardiovascular morbidity and mortality in CAD patients.33 The mean pre-training
value for the total group in our study was 5.44% (n = 156), which can be classified as
borderline impaired FMD and results in a 2.9 times higher risk of cardiovascular events
compared to an FMD >5.5%.33 This implies that the improvement in FMD to 6.58% is of
clinical relevance. The endothelial function increased significantly during the first 6 weeks of
the intervention, while further improvements were diminished between 6 and 12 weeks. It
seems that endothelial function adapts fast following exercise training, which confirms the
statement made in a review by Green et al.34
The absolute change in FMD correlated inversely with baseline FMD and positively with the
increase in peak VO2. These findings were also reported by Luk et al.28 and Wisloff et al.14,
and support the finding that endothelial function is a possible underlying mechanism in the
improvement of exercise capacity. Indeed, changes in peak VO2 following exercise training
result from increased O2 delivery (due to increased stroke volume and exercise-induced
vasodilation) and enhanced O2 consumption (increased oxidative capacity of skeletal
19
muscles). We observed no change in NMD following AIT or ACT, which is in line with other
studies.14,30 It seems that exercise primarily corrects the endothelial dysfunction and does
not improve the vascular smooth muscle cell responsiveness.28
Self-perceived QoL increased significantly and to a similar extent after AIT and ACT. There is
evidence that post-AMI patients have significant and clinically relevant poorer scores than
healthy subjects.21,35 Our CAD patients scored lower on the physical and mental component
compared to normative scores of the general Dutch population, even after the training
intervention.21 Our patients showed similar PCS scores21 but lower MCS scores21 compared to
a large sample of Dutch post-AMI patients. It seems reasonable to suggest that more
psychological support is necessary to normalize the self-perceived mental health.
HDL-C improved significantly in both groups, which is in contrast with findings in meta-
analyses on exercise training in CAD patients3,4 and other AIT versus MCT trials.36 Total
cholesterol, which consists of HDL-C, LDL-C and very LDL-C, increased after the intervention,
probably caused by the significant increment of HDL-C. Yet, the total / HDL cholesterol ratio
seems to be more informative about CAD mortality than total cholesterol or HDL-C either,
with a lower ratio predicting a lower mortality rate.37 In our study, the ratio showed a non-
significant decrease following the intervention. Hs-CRP decreased after the intervention,
which is in line with results of a meta-analysis of Swardfager et al. who found a significantly
reduced inflammatory activity after exercise training in CAD patients.38 Other laboratory
parameters did not change significantly because most of the patients were optimally treated
with lipid-lowering medication and anti-diabetic medication if necessary (see Table 1).
20
Finally, our results show that 6 weeks of three-weekly sessions of 38 minutes (duration of
one AIT session) are already sufficient to obtain clinically relevant improvements in peak
VO2, peripheral endothelial function and QoL. This is of interest to the patient as these
observed improvements might be an extra stimulus to continue a physically active lifestyle.
Furthermore we confirm that a longer training period resulted in further significant increases
in peak VO2 which stresses the need of encouraging a life-long physically active lifestyle not
only to further improve but at least to maintain the obtained improvements.39
Strengths and limitations
This study is strengthened by the large sample size (n=200), the repeated CPET after 6 weeks
to adapt the training intensity, the objective evaluation combined with the subjective
perception of the patients during the training sessions, and the multicentre design. Yet,
multicentre studies have limitations including the variability in assessments, analyses, and
implementation of training between the centres. In addition, caloric expenditure was not
measured, which could have been useful to compare the efficiency of the programs. Flow-
mediated dilation differed significantly between the centres (p<0.001) and was therefore
corrected in the analysis. Another limitation is the larger participation rate of men compared
to women, and moreover a larger drop-out in women.
Future research
Future research must focus on 1) the comparison of AIT and ACT performed at
representative and feasible intensities; 2) the underlying mechanisms responsible for peak
VO2 improvements; 3) the measurement of caloric expenditure of AIT and ACT or MCT used
in the present and in previous studies; 4) the comparison of AIT and ACT protocols with
21
other cardiac rehabilitation programs in terms of training response, long-term health, QoL
and patient satisfaction.
Conclusion
We can conclude that a 12-week AIT and ACT intervention equally improve peak VO2,
peripheral endothelial function, QoL and some cardiovascular risk factors in CAD patients. In
addition, both programs seem to be safe for CAD patients. In our experience, sustained AIT
at 90-95% of peak HR during four minutes is hardly feasible in CAD patients. When using
continuous exercise training, a sufficient training intensity should be performed, which may
be more than the 70-75% of peak HR of the baseline evaluation as used in a number of
previous studies. These conclusions should be taken into account when prescribing exercise
training programs in clinical practice.
Acknowledgements: This work was funded by the Agency of Innovation by Science and
Technology (IWT-project number 090870). VMC was supported by Research Foundation
Flanders (FWO) as a Clinical Postdoctoral Fellow, and VAC is supported by Research
Foundation Flanders (FWO) as a Postdoctoral Fellow. EVC is supported by Research
Foundation Flanders (FWO) as Senior Clinical Investigator. LV is the holder of the faculty
chair ‘Lifestyle and Health’ at the University of Applied Sciences, Utrecht, the Netherlands.
We want to thank Prof. V. Van Hoof, head of the Department of Clinical Biology of the
University Hospital of Antwerp, for the cooperation. In addition, we want to thank Inge
Goovaerts, Guy Ennekens and Katrijn Van Ackeren for the performance and analyses of the
endothelial function measurements in the University Hospital of Antwerp. Our thanks also
22
go to Yvette Piccart and Tamara Coenen for the processing of the blood samples in the
University Hospital of Leuven.
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References
1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and
regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a
systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;
380(9859):2095-128.
2. Nichols M, Townsend N, Luengo-Fernandez R, Leal J, Gray A, Scarborough P, Reyner
M. European Cardiovascular disease statistics 2012. European Heart Network,
Brussels, European Society of Cardiology.
3. Taylor RS, Brown A, Ebrahim S, Jolliffe J, Noorani H, Rees K. Exercise-based
rehabilitation for patients with coronary heart disease: systematic review and meta-
analysis of randomized controlled trials. Am J Med 2004; 116(10):682-92.
4. Oldridge N. Exercise-based rehabilitation in patients with coronary heart disease:
meta-analysis outcomes revisited. Future Cardiol 2012; 8(5):729-51.
5. Shepherd CW, While AE. Cardiac rehabilitation and quality of life: a systematic
review. Int J Nurs Stud 2012; 49(6):755-71.
6. Vanhees L, Fagard R, Thijs L, Amery A. Prognostic value of training-induced change in
peak exercise capacity in patients with myocardial infarcts and patients with coronary
bypass surgery. Am J Cardiol 1995; 76(14): 1014-9.
7. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity
and mortality among men referred for exercise testing. N Engl J Med 2002;
346(11):793-801.
24
8. Kavanagh T, Mertens DJ, Hamm LF, Beyene J, Kennedy J, Corey P, Shephard RJ.
Prediction of long-term prognosis in 12169 men referred for cardiac rehabilitation.
Circulation 2002; 106(6):666-71.
9. Keteyian SJ, Brawner CA, Savage PD, Ehrman JK, Schairer J, Divine G, Aldred H,
Ophaug K, Ades PA. Peak aerobic capacity predicts prognosis in patients with
coronary heart disease. Am Heart J 2008; 156(2):292-300.
10. Vanhees L, Rauch B, Piepoli M, van Buuren F, Takken T, Börjesson M, et al. Writing
group EACPR. Importance of characteristics and modalities of physical activity and
exercise in the management of cardiovascular health in individuals with
cardiovascular disease (Part III). Eur J Prev Cardiol 2012; 19(6):1333-56.
11. Mezzani A, Hamm LF, Jones AM, McBride PE, Moholdt T, Stone JA, et al. Aerobic
exercise intensity assessment and prescription in cardiac rehabilitation: a joint
position statement of the European Association for Cardiovascular Prevention and
Rehabilitation, the American Association of Cardiovascular and Pulmonary
Rehabilitation and the Canadian Association of Cardiac Rehabilitation. Eur J Prev
Cardiol 2013; 20(3):442-67.
12. Vanhees L, Stevens A, Schepers D, Defoor J, Rademakers F, Fagard R. Determinants of
the effects of physical training and of the complications requiring resuscitation during
exercise in patients with cardiovascular disease. Eur J Cardiovasc Prev Rehabil 2004;
11(4):304-12.
13. Rankin AJ, Rankin AC, MacIntyre P, Hillis WS. Walk or run? Is high-intensity exercise
more effective than moderate-intensity exercise at reducing cardiovascular risk?
Scott Med J 2012; 57(2):99-102.
25
14. Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo Ø, Haram PM, Tjønna AE,
Helgerud J, Slørdahl SA, Lee SJ, Videm V, Bye A, Smith GL, Najjar SM, Ellingsen Ø,
Skjaerpe T. Superior cardiovascular effect of aerobic interval training versus
moderate continuous training in heart failure patients: a randomized study.
Circulation 2007; 115(24):3086-94.
15. Keteyian SJ, Hibner BA, Bronsteen K, Kerrigan D, Aldred HA, Reasons LM, Saval MA,
Brawner CA, Schairer JR, Thompson TM, Hill J, McCulloch D, Ehrman JK. Greater
improvement in cardiorespiratory fitness using higher-intensity interval training in
the standard cardiac rehabilitation setting. J Cardiopulm Rehabil Prev 2014; 34(2):98-
105.
16. Pattyn N, Coeckelberghs E, Buys R, Cornelissen VA, Vanhees L. Aerobic interval
training vs. Moderate continuous training in coronary artery disease patients: a
systematic review and meta-analysis. Sports Med 2014: Epub ahead of print.
17. Conraads VM, Van Craenenbroeck EM, Pattyn N, Cornelissen VA, Beckers PJ,
Coeckelberghs E, De Maeyer C, Denollet J, Frederix G, Goetschalckx K, Hoymans VY,
Possemiers N, Schepers D, Shivalkar B, Vanhees L. Rationale and design of a
randomized trial on the effectiveness of aerobic interval training in patients with
coronary artery disease: the SAINTEX-CAD study. Int J Cardiol 2013; 168(4):3532-6.
18. Williams JR. The declaration of Helsinki and public health. Bull World Health Organ
2008; 86(8):650-2.
19. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et
al. Guidelines for the ultrasound assessment of endothelial-dependent flow-
mediated vasodilation of the brachial artery: a report of the International Brachial
Artery Reactivity Task Force. J Am Coll Cardiol 2002; 39(2):257-65.
26
20. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of
scales and preliminary tests of reliability and validity. Med Care 1996; 34(3):220-33.
21. Mols F, Pelle AJ, Kupper N. Normative data of the SF-12 health survey with validation
using post-myocardial infarction patients in the Dutch population. Qual Life Res 2009;
18(4):403-14.
22. Intention to treat analysis and per protocol analysis: complementary information.
Prescrire Int 2012; 21(133):304-6.
23. American College of Sports Medicine Position Stand. Exercise for patients with
coronary artery disease. Med Sci Sports Exerc 1994; 26(3): i-v.
24. Guiraud T, Juneau M, Nigam A, Gayda M, Meyer P, Mekary S, Paillard F, Bosquet L.
Optimization of high intensity interval exercise in coronary heart disease. Eur J Appl
Physiol 2010; 108(4): 733-40.
25. Aamot IL, Forbord SH, Karlsen T, Støylen A. Does rating of perceived exertion result in
target exercise intensity during interval training in cardiac rehabilitation? A study of
the Borg scale versus a heart rate monitor. J Sci Med Sport 2014; 17(5); 541-5.
26. Erbs S, Linke A, Hambrecht R. Effects of exercise training on mortality in patients with
coronary heart disease. Coronary Artery Dis 2006; 17(3): 219-25.
27. Edwards DG, Schofield RS, Lennon SL, Pierce GL, Nichols WW, Braith RW. Effect of
exercise training on endothelial function in men with coronary artery disease. Am J
Cardiol 2004; 93(5):617-20.
28. Luk TH, Dai YL, Siu CW, Yiu KH, Chan HT, Lee SW, Li SW, Fong B, Wong WK, Tam S, Lau
CP, Tse HF. Effect of exercise training on vascular endothelial function in patients with
stable coronary artery disease: a randomized controlled trial. Eur J Prev Cardiol 2012;
19(4): 830-9.
27
29. Cornelissen VA, Onkelinx S, Goetschalckx K, Thomaes T, Janssens S, Fagard R,
Verhamme P, Vanhees L. Exercise-based cardiac rehabilitation improves endothelial
function assessed by flow-mediated dilation but not by pulse amplitude tonometry.
Eur J Prev Cardiol 2014; 21(1):39-48.
30. Currie KD, Dubberley JB, McKelvie RS, MacDonald MJ. Low-volume, high-intensity
interval training in patients with CAD. Med Sci Sports Exerc 2013; 45(8):1436-1442.
31. Tjonna AE, Lee SJ, Rognmo Ø, Stølen TO, Bye A, Haram PM, Loennechen JP, Al-Share
QY, Skogvoll E, Slørdahl SA, Kemi OJ, Najjar SM, Wisløff U. Aerobic interval training
versus continuous moderate exercise as a treatment for the metabolic syndrome: a
pilot study. Circulation 118(4): 346-54.
32. Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky
ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in humans: a
methodological and physiological guideline. Am J Physiol Heart Circ Physiol 2011;
300(1): H2-12.
33. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, Saito Y, Kawabata K,
Sano K, Kobayashi T, Yano T, Nakamura K, Kugiyama K. Persistent impairment of
endothelial vasomotor function has a negative impact on outcome in patients with
coronary artery disease. J Am Coll Cardiol 2009; 53(4):323-30.
34. Green DJ, Maiorana A, O’Driscoll G, Taylor R. Effect of exercise training on
endothelium-derived nitric oxide function in humans. J Physiol 2004; 561(1):1-25.
35. Crilley JG, Farrer M. Impact of first myocardial infarction on self-perceived health
status. Q JM 2001; 94(1):13-18.
36. Moholdt TT, Amundsen BH, Rustad LA, Wahba A, Løvø KT, Gullikstad LR, Bye A,
Skogvoll E, Wisløff U, Slørdahl SA. Aerobic interval training versus continuous
28
moderate exercise after coronary artery bypass surgery: a randomized study of
cardiovascular effects and quality of life. Am Heart J 2009; 158(6):1031-7.
37. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P,
Emberson J, et al. Blood cholesterol and vascular mortality by age, sex, and blood
pressure: a meta-analysis of individual data from 61 prospective studies with 55,000
vascular deaths. Lancet 2007; 370(9602):1829-39.
38. Swardfager W, Herrmann N, Cornish S, Mazereeuw G, Marzolini S, Sham L, Lanctôt
KL. Exercise intervention and inflammatory markers in coronary artery disease: a
meta-analysis. Am Heart J 2012; 163(4):666-67.
39. Hansen D, Dendale P, van Loon LJ, Meeusen R. The impact of training modalities on
the clinical benefits of exercise intervention in patients with cardiovascular disease
risk or type 2 diabetes mellitus. Sports Med 2010; 40(11):921-40.
Figure legends
Figure 1. Visual presentation of the AIT (A) and ACT (B) program
a = 50–60% of peakVO2, 60–70% of peak heart rate, 11–13 Borg scale, no shortness of breath
b = 85–90% of peakVO2, 90–95% of peak heart rate, 15–17 Borg scale, shortness of breath
c = 50–70% of peak heart rate
d = at least 60–70% of peakVO2, at least 65–75% of peak heart rate
Figure 2. Flowchart of the trial
n = number of patients; CAD = coronary artery disease; LVEF = left ventricular ejection
fraction; AIT = aerobic interval training; ACT = moderate continuous training; F = female
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Figure 3. Percent changes in peak VO2 in AIT and ACT after 6 and 12 weeks.
Data are means ± SEM; * = significantly different from baseline (p<0.001); ** = 6 weeks
differs significantly from 12 weeks (p=0.0231); NS = not significant; black bars = AIT; grey
bars = ACT
Figure 4. Percent changes in flow-mediated dilation (%) in AIT and ACT after 6 and 12 weeks.
Data are means ± SEM; * = significantly different from baseline (0-6weeks: p=0.0122; 0-12
weeks: p=0.002); NS = not significant; black bars = AIT; grey bars = ACT
Potential conflicts of interest: There are no conflicts of interests to declare.
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